Aerosol composition

ABSTRACT

An aerosol composition comprising a propellant and a first particulate material comprising particle having a median aerodynamic diameter within the range 0.05 to 11 μm, such as a medicament suitable for pulmonary inhalation, and a second particulate material comprising particles having a median volume diameter within the range 15 to 200 μm. The presence of the second particulate material provides good suspension properties, particularly where the propellant is a hydrofluoro alkane.

The present invention relates to an aerosol composition. In particularthe present invention relates to an aerosol composition in the form of asuspension comprising liquid propellant and particulate material.

Effective use of an aerosol composition in the form of a suspensionusually requires the suspension to comprise a uniform dispersion ofparticulate matter in order to ensure the production of an aerosol ofknown components in known amounts. Inhomogeneous dispersions can occurdue to poor dispersibility of the particulate matter in the propellantand/or a tendency of the particulate matter to aggregate and possiblyeven to aggregate irreversibly.

Aerosol compositions comprising particulate matter in the form of asuspension can be used for the delivery of a number of active agents. Aparticular application comprises pharmaceutical suspensions foradministration of a drug in particulate form.

An example of a pharmaceutical application of a particulate-containingaerosol composition is inhaler suspensions. Inhaler suspensions are usedfor delivery of a particulate medicament to the lungs or upper airwaypassages. Suitably the suspension is contained in a container fittedwith a metering valve. A known dose can thus be administered on eachoccasion of use. Such containers can be convenient to use and arereadily portable.

Such a metered dose inhaler conventionally consists of a pressurisedcontainer which has a metering valve of fixed volume to measureindividual doses of a suspension of medicament held in the container. Inorder to ensure the administration of an accurate dose of suspendedparticulate medicament it is essential that the suspension isconsistently and homogeneously dispersed and the valve performance isreproducible and effective throughout the life of the container. Thesuspension conventionally comprises medicament particles dispersed in aliquefied gas which in use acts as a propellant. On depressing the valvestem of the metering valve the propellant fraction of the metered doserapidly vaporises so as to aerosolise the suspended particulatemedicament which is then inhaled by the user.

Traditionally, chlorofluorocarbons such as CFC-11, CFC-12 and CFC-114have been employed as propellants in metered dose inhalers. Aparticulate medicament intended for pulmonary administration needs tohave a particle size with a median aerodynamic diameter between about0.05 μm and about 11 μm. This range of size of medicament particle isimportant in inhalers. Larger particles will not necessarily or readilypenetrate into the lungs and smaller sized particles are readilybreathed out. However, particles between about 0.05 μm and about 11 μmcan possess a high surface energy and can therefore be difficult todisperse initially in the propellant, and once dispersed can exhibit atendency to aggregate undesirably and rapidly, leading eventually toirreversible aggregation of the particles. In the case of CFC as apropellant this problem was overcome by the addition of a surfactantsoluble in the CFC which coats the medicament particles and preventsaggregation by steric hindrance. The presence of surfactant is alsobelieved to be an aid to valve performance. In practice medicamentparticles were homogenised in the liquid CFC-11 with the inclusion of apropellant soluble surfactant such as lecithin, oleic acid or sorbitantrioleate. The resulting bulk suspension was dispensed into individualmetered dose inhalers and a high vapour pressure propellant such asliquefied gas CFC-12/CFC-114 added. Such arrangements provedsatisfactory in use, although the added surfactant could adverselyaffect the perceived taste of the inhaler in use. For example oleic acidcould impart a bitter taste.

In recent years the detrimental effect of chlorofluorocarbons on theozone layer in the earth's stratosphere has become apparent. Thecontinued use of CFC has therefore become unacceptable and in someinstances has been banned by local regulations.

Alternative propellants which share some similar physical properties tothose of previously used CFC propellants and which have been suggestedfor use in metered dose inhalers are hydrofluoroalkanes, notablyHFA-134a and HFA-227. Problems however exist on attempting to formulatethe hydrofluoroalkanes into an aerosol composition such as an inhalersuspension. Firstly, the acceptable surfactants employed in CFC basedsuspensions are not sufficiently soluble in hydrofluoroalkanes toprevent irreversible aggregation of the particulate medicamentoccurring. Secondly, neither HFA-134a nor HFA-227 is a liquid at anacceptable temperature so that bulk homogenisation with particulatematerial prior to filling into individual pressured containers is onlypossible if carried out under pressure.

A number of proposals have been made in an attempt to employhydrofluoroalkanes as the propellant in pressurised metered doseinhalers for example a patent specification (WO 92/06675) in the name ofMinnesota Mining and Manufacturing Company suggests the use ofnon-volatile co-solvents to modify the solvent characteristics of thehydrofluoroalkane propellant and thereby increase the solubility andhence permit the use of the surfactants traditionally employed in CFCbased metered dose inhalers. The presence of the co-solvent however mayresult in less desirable aerosol properties. Moreover the alcoholnonvolatile co-solvents suggested can impart an unpleasant sharp taste.

Patent specifications (WO 91/11173 and WO 92/00061) in the name ofFisons suggest the use of alternative surfactants which are sufficientlysoluble in HFA-134a and HFA-227. The surfactants proposed however maypresent toxicity problems in use. Extensive and expensive toxicitystudies are therefore required before the pharmaceutical regulatoryauthorities will permit their inclusion in a product intended for humanuse.

Glaxo Group Limited in WO 96/19968 suggests a pharmaceutical aerosolformulation which comprises particulate medicament, at lease one sugarand a fluorocarbon or hydrogen containing chlorofluorocarbon propellant.The particle size of the sugars used in the formulations are said to beselected using conventional techniques such as milling or micronisation.The suspension stability of the aerosol formulations is said to beparticularly impressive.

Other proposals to provide a metered dosed inhaler employinghydrofluoroalkane are found in patent specification no. WO 92/08477 inthe name of Glaxo Group Limited and patent specification no. EP 372777in the name of Riker Laboratories, Inc.

A need therefore exists to provide an aerosol composition suitable foruse in for example, an inhaler, comprising a suspension of particulatematter in a propellant, which composition has good dispersioncharacteristics, a reduced tendency to aggregate and can in use beeffectively aerosolised with good valve performance.

It is an object of the present invention to provide an aerosolcomposition including a particulate material suitable for use in forexample an inhaler which composition exhibits both a reduced tendencyfor the particulate material to aggregate undesirably and ready andhomogeneous dispersion of the particulate material, and permitsacceptable delivery of the particulate material.

It is a further object of the present invention to provide an additivecomprising a particulate material for use in the preparation of such anaerosol composition.

It is a further object of the present invention to provide a container,such as an inhaler, containing such a composition.

It is a further object of the present invention to provide a container,such as metered dose inhaler incorporating a valve dispensing mechanism,containing such a composition, the composition ensuring both goodsuspension properties and good valve performance over the life of thecontainer.

Further objects of the present invention include a method of preparing acontainer containing such a composition and a method of administeringthe composition.

According to a first aspect of the present invention there is providedan aerosol composition comprising a propellant and contained therein afirst particulate material comprising particles having a medianaerodynamic diameter within the range 0.05 to 11 μm and a secondparticulate material comprising particles having a median volumediameter within the range 15 to 200 μm.

The propellant is in liquid form during storage of the composition andevaporates in use. The inclusion of a second particulate material havinga median volume diameter in the range 15 to 200 μm in combination withthe first particulate material having a median aerodynamic diameter inthe range 0.05 to 11 μm has unexpectedly been found to enhancedispersion and to reduce particulate aggregation, leading to a reducedrisk of irreversible aggregation, whilst still permitting good aerosolperformance of the suspension in use. The result is unexpected as primafacie the inclusion of extra insoluble solids had been considered to beinappropriate leading to less desirable aerosol characteristics and poorvalve performance due for example to blocking. The present invention canthus permit the delivery of particulate material at a known andconsistent concentration.

Although we do not wish to be bound by any theory we believe that thepresence of the second particulate material having a median volumediameter in the range 15 to 200 μm reduces the risk of irreversibleaggregation of the first particulate material as the larger particlesare unable to pack sufficiently close together to permit packing ofparticles in the primary energy minimum. By “irreversible aggregation”we mean aggregation of particles which cannot be dispersed by hand heldshaking.

Within the aerosol composition the first and second particulatematerials are believed to be present as either a simple admixture orwith some or all of the smaller first particulate material particlesinteracting with the larger particles of the second particulatematerial. The presence of the second particulate material can thus helpto prevent non-specific adsorption of the first particulate material tothe inside surface of a container containing the aerosol composition andto break up any aggregates of the first particulate material that mayform.

The presence of the second particulate material in the propellant canlead to flocculation i.e. loose association of the suspended particlesinto a fluffy floc. Flocculation differs from irreversible aggregationin that it occurs in the secondary energy minimum and is dispersible byhand held shaking. Flocculation of the second particulate material canoccur in the propellant either in the absence or in the presence of thefirst particulate material. Where flocculation occurs in the absence ofthe first particulate material, the equivalent composition containingadditionally the first particulate material can surprisingly inhibit theflocculation occurring. Where flocculation of the second particulatematerial does however occur in the propellant in the presence of thefirst particulate material it is not detrimental to the presentinvention as it can be removed by hand held shaking prior to use of theaerosol. It may moreover even be beneficial in preventing irreversibleaggregation in the primary energy minimum.

By “volume diameter” is meant the diameter of a sphere having the samevolume as the particle. The second particulate material is selectedaccording to its volume diameter as it is the physical bulk of thesecond particulate material which is believed to be important indetermining the properties of the suspension.

By “aerodynamic diameter” is meant the volume diameter multiplied by thesquare root of the ratio of the particle density (g cm⁻³) to the densityof a particle with same volume diameter having a density of 1 g cm⁻¹.The first particulate material is thus selected according to its volumediameter having the stated consideration for its density. In thedefinition of “aerodynamic diameter” given above the assumption is made,in keeping with conventional aerosol practice, that the firstparticulate material can be deemed to be spherical in shape. Moreover,where as is usually the case, the first particulate material has aparticle density between about 1 and 2 g cm⁻³ the aerodynamic diameterof the first particulate material is approximately equivalent to itsvolume diameter

According to another aspect of the present invention there is provided acontainer containing the aerosol composition according to the presentinvention, the container including a valve outlet. Suitably the contentsof the container are pressurised up to a pressure of 6.893×10⁵Pa (100psig). Preferably the container includes a metered valve outlet capableof delivering a measured dose of suspension in the form of an aerosol.Preferably the container is in the form of an inhaler. According toanother aspect of the present invention there is provided an inhalationdevice incorporating the said container.

According to another aspect of the present invention there is provided amethod for preparing an aerosol composition comprising:

(a) forming a mixture of a first particulate material comprisingparticles having a median aerodynamic diameter within the range 0.05 to11 μm and a second particulate material having a median volume diameterwithin the range 15 to 200 μm;

(b) dispensing measured portions of respectively said mixture and apropellant into a container, and

(c) scaling the container.

Alternatively all of the ingredients can be admixed prior to dispensinginto individual containers.

Suitably the container is pressurised and includes an outlet valve,preferably a metered dose dispensing valve.

The mixture of the first particulate material and the second particulatematerial permits ready dosing of the mixture into the container due toimproved flow characteristics compared to the first particulate materialin the absence of the second particulate material. Suitably the mixtureis dosed into the container before the propellant. The enhanceddispersion characteristics of the mixture in the added propellantpermits the omission of the step of providing a homogeneous suspensionprior to dispensing into a container. In keeping with conventionalprocedures for preparing an aerosol the container can be sealedfollowing the dosing of the mixture into the container, with thepropellant being subsequently dosed into the container through forexample an outlet valve forming a part of a seal.

According to another aspect of the present invention there is provided amixture of a first particulate material having a median aerodynamicdiameter within the range 0.05 to 11 μm and a second particulatematerial having a median volume diameter within the range 15 to 200 μm.

According to another aspect of the present invention there is provided ause of a particulate material, for example lactose, having a medianvolume diameter lying in the range 15 to 200 μm to enhance thedispersion characteristics of a particulate material having a medianaerodynamic diameter lying in the range 0.05 to 11 μm in suspension in apropellant.

According to another aspect of the present invention there is provided amethod of administering a particulate material to a patient in needthereof comprising the patient inhaling an aerosol comprising vaporisedpropellant and a mixture of an active agent comprising particles havinga median aerodynamic diameter lying in the range 0.05 to 11 μm and asecond particulate material comprising particles having a median volumediameter lying in the range 15 to 200 μm. In applying the method, forcesgenerated by vaporisation of the propellant separate particulate activeagent from the mixture such that the active agent is available andsuitable for lung deposition after inhalation. The method can be appliedorally or nasally.

According to another aspect of the present invention there is providedan aerosol composition comprising a mixture of an active agentcomprising particles having a median aerodynamic diameter lying in therange 0.05 to 11 μm and a second particulate material comprisingparticles having a median volume diameter lying in the range of 15 to200 μm for use in the treatment of respiratory diseases.

Preferably the first particulate material has a median aerodynamicdiameter within the range 1 to 10 μm, more preferably within the range 1to 5 μm. Where the present aerosol composition is employed as an inhalersuch preferred ranges are optimum for respiratory delivery.

Preferably the second particulate material has a median volume diameterof more than 20 μm suitably within the range 20 to 125 μm, morepreferably within the range 25 to 125 μm, even more preferably withinthe range 30 to 125 μm, even more preferably still within the range 38to 125 μm. Preferred ranges may moreover include 45 to 125 μm and 63 to125 μm.

Suitably the second particulate material is sufficiently soft to ensurethat no or minimal damage, for example, such as scratching is sustainedby the valve over the lifetime of, for example, a metered dose inhaler.A metered dose inhaler may have the potential to provide in excess ofone hundred shots or actuations and ideally needs to be reproducible ata pattern of usage of two shots four times daily. Absence of anysignificant damage to the valve is essential to ensure that over thelifetime of the container a sufficiently consistent shot or actuation ofeach dose of homogeneous suspension is provided to ensure appropriateand sufficiently accurate delivery of, for example, medicament as thefirst particulate material.

A sufficiently soft second particulate material would also reduce thelikelihood of valve leakage potentially attributable to particulatematerial lodging in the valve head and preventing proper reseating ofthe valve after each use. Preferable the softness of the secondparticulate material is less than 6.5 Mohs hardness, more preferablyless than 5 Mohs hardness, even more preferably less than 4 Mohshardness and even more preferably less than 3 Mohs hardness. The minimumMohs hardness is 0. The preferred range is between 2 to 4, the morepreferred range is 2 to 3 Mohs hardness.

Performance of the valve in a pressurised container containing thepresent composition may additionally and/or alternatively be adverselyaffected by the shape of the particle comprising the second particulatematerial. Preferably the second particulate material is substantiallyspheroidal or ellipsoidal. Although we do not wish to bound by anytheory, it is postulated that a second particulate material having agenerally curved outline will ensure better valve performance due to areduce likelihood of, for example, scratching of the valve head leadingto, possibly, valve leakage and/or inaccurate valve metering. Theoptimum combination of shape and softness of any second particulatematerial will, however, be dependent on the material in question and thevalve head employed. For example, especially soft second particulatematerial may yield the necessary good suspension and dispersionproperties in the aerosol composition contained in the container priorto use, and yet give no or minimal value damage, even through theparticles in the second particulate material are substantiallynon-spherodial or non-ellipsoidal, for example are in the shape ofplates or discs.

The Carr Index is a measure of flow properties of a material in powderform and is substantially dependent on the shape and size of theparticles comprising the powder. The Carr Index is defined as:$\frac{\text{tapped density} - \text{poured density}}{\text{tapped density}} \times 100\%$

The Carr Index is measured at 25° C. and compares the density of apowder material when poured into a container with the density of thesame material in the same container after the container has been tappedand the powder material has settled to a substantially plateau value.

Preferably the Carr Index for particles comprising the secondparticulate material and having a population predominantly (i.e. >50%)more than 100 μm in diameter is less than 14%, more preferably less than12%, even more preferably less than 10%.

Preferably the Carr Index for particles comprising the secondparticulate material and having a population predominantly (i.e. >50%)less than 100 μm in diameter is less than 28%, more preferably less than26%, even more preferably less than 24%.

Preferably the Carr Index for particles comprising the secondparticulate material and having a population predominantly (i.e. >50%)less than 40 μm in diameter is less than 35%, more preferably less than33%, even more preferably less than 31%.

Preferably the Carr Index for particles comprising the secondparticulate material and having a population predominantly (i.e. >50%)less than 20 μm in diameter is less than 65%, more preferably less than63%, even more preferably less than 61%.

Preferably the weight ratio of the first particulate material to thesecond particulate material lies in the range 1:0.1 to 1:500, the weightbeing that of the first particulate material and the weight of thesecond particulate material admixed with the propellant and thusincludes any material dissolved in the propellant. More preferably theweight ratio of the first particulate material to the second particulatematerial lies in the range 1:1 to 1:200, even more preferably within therange 1:10 to 1:100, even more preferably within the range of 1:25 to1:67. The actual ratio selected for any particular suspension willdepend inter alia on the solubility of each of the first and secondparticulate materials in the propellant, the dosage or usagerequirements of the particulate materials and the extent of anyinteraction between the first particulate material and the secondparticulate material. An alternative preferred range of the weight ratioof first to second particulate material is 1:5 to 1:50.

The actual amount and size of each particulate material used will dependinter alia on the solubility of each particulate material in thepropellant and the type and dose of each particulate material required.Suitably however the aerosol composition comprises 80 to 99.999 wt %propellant, more suitably 90 to 99.9 wt % propellant. The total weightof particulate material employed, measured as including dissolved andundissolved material, is thus suitably 20 to 0.001 wt % with respect tothe total weight of the composition, more preferably 10 to 0.1 wt % withrespect to the total weight of the composition. The concentration of thefirst particulate material in the composition, including dissolved andundissolved material, preferably lies in the range 1 to 0.0001 wt %,more preferably in the range 0.5 to 0.005 wt % with respect to the totalweight of the composition.

Each of the first and second particulate materials may be partiallysoluble in the propellant. Preferably the solubility of the firstparticulate material in the propellant does not exceed 49.9 wt % withrespect to the total weight of the substance comprising the firstparticulate material present. More preferably the solubility of thefirst particulate material in the propellant does not exceed 10 wt %,even more preferably 1.0 wt % with respect to the total weight of firstparticulate material present.

Preferably the solubility of the second particulate material in thepropellant does not exceed 49.9 wt % with respect to the total weight ofthe substance comprising the second particulate material present. Morepreferably the solubility of the second particulate material does notexceed 10 wt %, even more preferably 1.0 wt % with respect to the totalweight of the second particulate material present. Low solubility ofeach of the first particulate material and the second particulatematerial is preferred in order to avoid stability problems such as therisk of particle growth due to Ostwald ripening.

Preferably the ratio of the density of the second particulate materialto the density of the propellant lies in the range 0.6:1 to 1:1.6. Toolarge a density difference between the density of the second particulatematerial and the density of the propellant is preferably avoided. Theoptimal density difference can be ascertained in each instance,particularly having regard to the ambient temperature effecting thedensity of the propellant and any tendency of the second particulatematerial to flocculate in the presence of the first particulatematerial. When not equal to the density of the propellant the density ofthe first particulate material and the density of the second particulatematerial are in some instances suitably both either more than or lessthan the density of the propellant. Should the first and secondparticulate materials exhibit any tendency to sediment or cream (i.e.float) their uniform dispersion in the propellant can thus be morereadily achieved.

The substance comprising the second particulate material is suitablychemically unreactive with respect to the first particulate material.The present aerosol composition can be in the form of a pharmaceuticalcomposition. Where the first particulate material is a medicament, thesecond particulate material preferably does not modify thebiopharmaceutical profile of the medicament comprising the rustparticulate material. The second particulate material can comprise oneor more active or inactive agents or a mixture thereof, for example itcan comprise one or more pharmacologically inert substances, one or morepharmacologically active substances, one or more flavour impartingsubstances or a mixture thereof. Where the present aerosol compositionis intended for use as an inhaler, the second particulate material canfor example comprise a pharmacologically active substance for oraladministration.

Where the first particulate material is a medicament, the secondparticulate material should be acceptable for administration to a human.Preferably it will be a substance which already possesses regulatoryapproval and has a desirable safety profile. For example where thepresent aerosol composition is intended for use as an inhaler the secondparticulate material may already possess regulatory approval for use inpulmonary administration. The second particulate material selectedshould preferably be relatively inexpensive and readily available.

Suitable substances for use as the second particulate material in atleast an inhaler may be selected from carbohydrates such as sugars,mono-, di-, tri-, oligo- and poly-saccharides and their reduced formssuch as sorbitol; from amino acids, di-, tri-, oligo- and poly-peptidesand proteins; and from physiologically acceptable derivatives, forms,salts and solvates thereof; and from mixtures thereof. Preferably thesecond particulate material is selected from lactose, glucose andleucine and mixtures thereof. The material can be in any appropriateform, for example lactose can be α-lactose, β-lactose, anhdrous lactose,amorphous or any form of lactose or any mixture thereof. Leucine andspray dried lactose are especially preferred where valve performance maybe of importance as they are each relatively soft. Spray dried lactoseadditionally is substantially spheroidal and may be preferred wherevalve performance is of importance.

Where the first particulate material is a particulate medicamentsuitable for oral or nasal inhalation and the aerosol composition isintended for use as an inhaler, examples of suitable particulatemedicaments for use in the treatment and prevention of asthma and otherconditions associated with reversible airways obstruction include eitheralone or in any combination:

(i) salbutamol, salbutamol sulphate, mixtures thereof andphysiologically acceptable salts and solvates thereof,

(ii) terbutaline, terbutaline sulphate, mixtures thereof andphysiologically acceptable salts and solvates thereof,

(iii) beclomethasone dipropionate and physiologically acceptablesolvates thereof,

(iv) budesonide and physiologically acceptable solvates thereof,

(v) triamcinolone acetonide and physiologically acceptable solvatesthereof,

(vi) iprawtopium bromide and physiologically acceptable salts andsolvates thereof, and

(vii) corticosteriod or bronchodilator.

Other examples of particle medicaments suitable for oral or nasalinhalation by means of the present aerosol composition include:

(viii) peptides, proteins, nucleic acids and derivatives thereof for usein the treatment and prevention of disease states,

(ix) insulin, calcitonin, growth hormone, lutenising hormone releasehormone (LHRH), leuprolide, oxytocin and physiologically acceptablesalts and solvates thereof for use in the treatment and prevention ofdisease states including diabetes, and

(x) any pharmacologically active particulate medicament having a medianaerodynamic diameter within the range 0.05 to 11 μm administered in theform of an aerosol.

Further examples of appropriate medicaments may additionally be selectedfrom, for example, analgesics, e.g., codeine, dihydromorphine,ergotamine, fentanyl or morphine; anginal preparations, e.g., diltiazem;antiallergics, e.g., cromoglycate, ketotifen or nedocromil;anti-infectives e.g., cephalosporins, penicillins, streptomycin,sulphonamides, tetracyclines and pentamidine; antihistamines, e.g.,methapyrilene; anti-inflammatories, e.g., beclomethasone dipropionate,fluticasone propionate, flunisolide, budesonide, rofleponide, mometasonefuroate or triamcinolone acetonide; antitussives, e.g., noscapine;bronchodilators, e.g., albuterol, salmeterol, ephedrine, adrenaline,fenoterol, formoterol, isoprenaline, metaproterenol, pbenylephrine,phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline,isoetharine, tulobuterol, or(−)4-amino-3,5-dichlor-α[[[6-[2-(2-pyridinyl)ethoxy] hexyl]methyl]benzenemethanol; diuretics, e.g., amiloride; anticholinergies, e.g.,ipratropium, iotropium, atropine or oxitropium; hormones, e.g.,cortisone, hydrocortisone or prednisolone; xanthines, e.g.,aminophylline, choline theophyllinate, lysine theophyllinate ortheophylline; therapeutic proteins and peptides e.g., insulin orglucagon. It will be clear to a person skilled in the art that, whereappropriate, the medicaments may be used in the form of salts, (e.g., asalkali metal or amine salts or as acid addition salts) or as esters(e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimisethe activity and/or stability of the medicament.

Preferred medicaments are selected from albuterol salineterol,fluticasone propionate and beclometasone dippropionate and salts orsovates thereof, e.g., the sulphate of albuterol and the xinafoate ofsalmeterol.

Medicaments can also be delivered in combinations. Preferredformulations containing combinations of active ingredients containsalbutamol (e.g., as the free base or the sulphate salt) or salmeterol(e.g., as the xinafoate salt) in combination with an anti-inflammatorysteroid such as a beclomethasone ester (e.g., the dipropionate) or afluticasone ester (e.g., the propionate).

The dosage requirements for any one medicament will be thoseconventionally employed in inhalers. For example where the firstparticulate material is salbutamol for use in relation to asthma theinhaler is employed as required, usually 1 or 2 actuations (i.e. puffs)between 0 and 4 times per day, with a single metered dose comprising 100micrograms of salbutamol in a volume of metered liquid propellantbetween 20 and 150 μl.

The propellant is preferably selected from chlorofluorocarbons, fromhydrofluorocarbons and from mixtures thereof. When the propellant is achlorofluorocarbon such as CFC-11, CFC-12, CFC-114 the present inventioncan provide a suspension that obviates the need for the addition ofunpalatable, or possibly even mildly toxic, surfactant. Alternativelythe propellant can comprise hydrofluoroalkane such as1,1,1,2-tetrafluoroethane (HFA-134a), 1,1,1,2,3,3,3-heptafluoropropane(HFA-227) and mixtures thereof. The combination of the first particulatematerial with the second particulate material both reduces the risk ofthe first particulate material aggregating undesirably and enhances thedispersement of the particulate medicament in the propellant. Inmanufacturing individual units of the suspension the increaseddispersibility provided by the present invention obviates the need toprepare an initial bulk suspension by a homogenisation step. Thecombination of the first particulate material and the second particulatematerial can be readily wetted by and dispersed in HFA propellants inthe absence of surfactant or added co-solvent. The suitable dispersioncharacteristics in HFA displayed by the presently provided combinationof particulate materials permits its initial dispersion and anyredispersion required following sedimenting or creaming with a smallenergy input, e.g. hand held shaking.

The present suspension can optionally contain any additional appropriateingredients, for example pharmacologically acceptable excipients such asa surfactant, flavouring, buffer and preservatives in conventionalacceptable amounts.

Embodiments of the present invention will now be described by way ofexample only with reference to the following Examples and theaccompanying figures wherein:

FIG. 1 is a vertical cross section of a metered dose inhaler;

FIG. 2 is a vertical cross sectional view of the spring mechanism of themetered dose inhaler of FIG. 1;

FIG. 3 is a diagram showing the shot weights during the lifetime ofthree meter dosed inhalers;

FIG. 4 is a diagram showing shot potency over the lifetime of a metereddosed inhaler; and

FIG. 5 is a diagram showing aerosol performance over the lifetime of ametered dose inhaler.

The present embodiments relate to an aerosol composition in the form ofan inhaler.

COMPARATIVE EXAMPLES A TO T

Examples A to Q are comparative examples and demonstrate the suspensionproperties of a variety of particulate materials in the absence of amedicament.

Each suspension was assessed visually for its ease of dispersion on handheld shaking, its extent of aggregation and the quality of thesuspension.

Ease of dispersion was scored on a scale of good (g), medium (m) andpoor (p).

The extent of aggregation was scored on a scale of low, medium and high.Additionally the type of aggregation, if present, was recorded.

The quality of the suspension was scored on a scale of poor (p),poor-fair (p/f), fair (f), fair-good (f/g) and good (g).

Table I below gives the suspension properties of two types of lactoseacross a range of particle size. Example A employed a sample of acommercially available α-lactose monohydrate, “Lactochem (RTM) Regularfor Inhalation” ex. Borculo of Chester, England. The particle sizefractions of Examples B to G were achieved by sieving the commerciallyavailable lactose powder employed in Example A. Example H employed acommercially available αm-lactose monohydrate “Lactochem (RTM) Microfinefor Inhalation”. The particle size fractions employed in Examples I to Mwere achieved by sieving a commercially available lactose powder knownas “Super-Tab” ex. Lactose New Zealand.

The sieved diameters were taken to be substantially equivalent to thevolume diameter. The median particle diameter of the fraction employedin Example G comprising <38 μm particles of lactose was approximately 17to 18 μm. The fraction employed in Example H comprising <10 μm particlesof lactose had a median particle diameter of about 2.5 to 3.0 μm.

Each example comprised a suspension of 0.83 w/w % of lactose powder and99.17 ww % of HFA-134a, which is 1,1,1,2-tetrafluoroethane.

TABLE I Size of Eau of Exam- Particulate Particle Disper- Extent ofSuspension ple Material (μm) sion Aggregation Quality A lactose  4-400 glow f/g B lactose >125 g low f C lactose 125-90  g low f/g D lactose90-63 g low f/g E lactose 63-45 g medium- f flocculation F lactose 45-38g high p/f flocculation G lactose  <38 g high- p/f flocculation Hlactose  <10 p/f high- p flocculation and irreversible aggregation Ilactose - >125 g Low p/f spray dried J lactose - 125-90  g Low f spraydried K lactose - 90-63 g low/medium- f/g spray dried flocculation Llactose - 63-45 g medium/ p/f spray dried high- flocculation M lactose - <45 g high- p/f spray dried flocculation

As can be seen from the results in Table I each type of lactosedisplayed good dispersion properties, apart from Example H, and atlarger particle sizes low aggregation and at smaller particle sizes avarying degree of flocculation. The suspension quality varied across thesize range of particulate lactose peaking for each type at mid-rangesizes. Example H however exhibited aggregates which could not bedispersed by hand held shaking.

Table II below gives the suspension properties of two furtherparticulate materials each of which has a particle size volume diameterin the range of 125 to 90 μm. The leucine employed was L-leucine ex.Sigma of Poole, England. The glucose was d-glucose anhydrous ex. Fisonsof Loughborough, England. A suspension was formed with each particulatematerial with each of HFA-134a, which is 1,1,1,2-tetrafluoroethane, andHFA-227, which is 1,1,1,2,3,3,3heptafluoropropane, as propellant.

TABLE II Particulate Exam- material Propellant Ease of Extent ofSuspension ple (w/w%) (w/w%) Dispersion aggregation Quality N leucineHFA-134a g medium- g (0.83) (99.17) flocculated O leucine HFA-227 glow/medium- g (0.71) (99.29) flocculated P glucose HFA-134a g medium-f/g (0.83) (99.17) flocculated Q glucose HFA-227 g medium- f/g (0.71)(99.29) flocculated

Leucine is less dense than either of the propellants employed and had atendency to cream i.e. rise to the surface of the propellant. Glucose ismore dense than either of the propellants employed and had a tendency tosediment. In all cases however flocculated and other separatedparticulate material could be formed into a suspension on hand heldshaking.

Examples R, S and T are comparative examples and demonstrate thesuspension properties of a variety of particulate medicaments in thepropellant HFA-134a in the absence of any second particulate material.The suspension properties measured by visual inspection were ease ofdispersion, extent of aggregation and suspension quality and were scoredas for Examples A to Q.

The results and compositions employed are given in Table III below. Themedian particle size given for each particulate medicament is its medianvolume diameter, which in each case is deemed approximately equivalentto the median aerodynamic diameter.

TABLE III Median Particulate size Suspen- medicament of particle Ease ofExtent of sion Example (w/w %) (μm) dispersion aggregation quality RSalbutamol 2.71 poor high poor (0.08) S Salbutamol 3.57 poor high poorsulphate (0.08) T Budesonide 1.83 poor high poor (0.17)

Each of Examples R, S and T exhibited poor dispersion and poorsuspension qualities. In each case the majority of the particulatemedicament was present in about 20 aggregates, which could not bedeaggregated by hand held shaking.

EXAMPLES 1 TO 22 EMBODYING THE PRESENT INVENTION

The metered dose inhaler shown in the accompanying FIGS. 1 and 2 indiagrammatic form comprises an inverted container (1) and a meteringvalve (2). The inverted container (1) is capable of withstanding apressure up to 6.895×10⁵Pa (100 psig) and is closed by a closure cap(3). The metering valve (2) extends through the closure cap (3) andincludes a fixed volume chamber (4), a spring mechanism (5) biased tomaintain the valve closed when not being actuated and an outlet stem (6)which opens into an expansion chamber (7). The container (1) andmetering valve (2) are mounted by support (8) in a holder (9) which isintegral with an actuator tube (10) extending at an obtuse angle awayfrom the holder (9). As can be seen in the drawing the expansion chamber(7) opens by way of a spray jet orifice (11) into the actuator tube(10). The container (1) contains the aerosol composition (12) comprisingpropellant and suspended particulate matter.

In use the container (1) is depressed relative to the holder (9) causingthe chamber (4) to be open to the atmosphere and the fixed volume ofliquefied gas therein to expand forcing the suspension into theexpansion chamber (7) where the liquefied gas continues to expand andevaporate. The actuator tube (10) directs the aerosol so produced intothe mouth or nose of the patient, as required for inhalation.

EXAMPLES 1 TO 7

Examples 1 to 7 demonstrate the suspension and aerosol properties for arange of compositions varying in the particulate medicament, the secondparticulate material having regard to both its particle size and itskind, and the propellant employed. The particulate size given in TableIV below for each of the medicaments is the mean volume diameter, whichis deemed approximately equivalent to the mean aerodynamic diameter. Thelactose particulate fractions employed were derived by sieving thecommercially available product employed in Example A above, the sievedparticle size were taken to be equivalent to the mean volume diameters.The leucine,and glucose particulate material employed were the same asthose employed in Examples N and P above respectively, the particulatesize given in Table IV below being the volume diameter.

In each of Examples 1 to 7 the particulate medicament is mixed togetherwith the second particulate material by hand mixing in a mortar with asteel spatula at a ratio of particulate medicament to second particulatematerial of 1:10. The resulting mixture is dosed into the container ofthe metered dose inhaler described above, the closure cap crimped inplace and the propellant added, as indicated in Table IV below. Thebalance of each composition comprised the 1:10 mixture of theparticulate medicament and the second particulate material.

The resulting suspensions were assessed visually for ease of dispersion,suspension quality and extent of aggregation and scored as above, as setout under Examples A to R. The results are given in Table IV below.

Additionally, the shot weight and the aerosol characteristic of eachsuspension were assessed. The aerosol characteristics of each suspensionwere assessed using a 4 stage liquid impinger or Copley twin stageimpinger operated at 60 L/min and the fine particle fraction, whichprovides an indication of the proportion of aerosol likely to reach apatient's lungs, recorded. A score of at least 40% was marked as good(g), 30-40% as fair (f) and less than 30% as poor (p).

The shot weight i.e. the weight of suspension metered with eachactuation of the valve, was assessed. In each case the shot weight wasfound to be reproducible indicating no adverse clogging or blocking ofthe valve mechanism.

TABLE IV Second Fine Particulate particulate Propel- Ease of particlemedicament material lant Disper- Extent of Suspension fraction Example(μm) (μm) (w/w %) sion Aggregation Quality of aerosol 1 budesonidelactose HFA- g low f/g f/g (1.83) (90-63) 134a (99.09) 2 salbutamollactose HFA- g low f/g g sulphate (90-63) 227 (3.57) (99.29) 3salbutamol lactose HFA- g low f/g g sulphate (125-90) 227 (3.57) (99.29)4 salbutamol leucine HFA- g medium- f/g g sulphate (125-90) 113aflocculated (3.57) (99.17) 5 salbutamol leucine HFA- g medium- f/g gsulphate (125-90) 227 flocculated (3.57) (99.29) 6 salbutamol glucoseHFA- g low/ f/g g sulphate (125-90) 134a medium- (3.57) (99.17)flocculated 7 salbutamol glucose HFA- g medium- f/g g sulphate (125-90)227 floculated (3.57) (99.29)

For each of Examples 1 to 7 the scores given in Table IV indicate acomposition having acceptable suspension and aerosol properties. Theflocculated material in each of Examples 4 to 7 could be dispersed byhand held shaking.

EXAMPLES 8 TO 21

In each of the following Examples 8 to 14, 20 and 21 commerciallyavailable lactose powder as used in Example A above was employed as thesecond particulate material. In each of following Examples 15 to 19commercially available lactose as employed in example A above wasemployed as the source of the lactose fractions used. The powder asreceived had a median volume diameter particle size of 80 μm. The rangeof volume diameter in the commercially available product was 4 to 400μm.

The propellant employed in each of Examples 8 to 21 was HFA-134a whichchemically is 1,1,1,2-tetrafluoroethane.

Examples 8 to 11 and Examples 13 and 20 contained salbutamol as aparticulate medicament. The particulate salbutamol had a median volumediameter of 2.71 μm which is approximately equal to the medianaerodynamic diameter for salbutamol.

Examples 12, 14 to 19 and 21 contained salbutamol sulphate as aparticulate medicament. The particulate salbutamol sulphate had a medianvolume diameter of 3.57 μm, which in the case of salbutamol sulphate isapproximately equal to the median aerodynamic diameter.

The particulate components of each of Examples 8 to 21 were dosed asindicated below and mixed together by hand mixing in a mortar with asteel spatula. The mixture was dosed as indicated below into atransparent container of a metered dose inhaler as described above, ametering valve crimped in place and the container filled with propellantas indicated below.

The suspensions so formed were assessed visually for ease of dispersionand suspension quality and each assessment was scored on a scale of poor(p), poor-fair (p/f), fair (f), fair-good (f/g), good (g).

The extent of aggregation of each suspension was also assessed visuallyand in each example was rated as low.

The shot weight i.e. the weight of suspension metered with eachactuation of the valve, was assessed. In each case the shot weight wasfound to be reproducible indicating no adverse clogging or blocking ofthe valve mechanism.

The aerosol characteristics of each suspension of Examples 8 to 19 wereassessed using a 4 stage liquid impinger or Copley twin stage impingeroperated at 60 L/min and the fine particle fraction, which provides anindication of the proportion of aerosol likely to reach a patient'slungs, recorded. A score of at least 40% was marked as good (g), 30-40%as fair (f), and less than 30% as poor (p).

Examples 8 to 13 investigate the effect of the weight ratio of theparticulate medicament to particulate lactose in the initial blend ofparticulate components by varying the ratio through the range 1:2.5 to1:100. The overall composition in terms of the amount of propellantadded was determined having regard to providing a therapeutic dose ofmedicament per actuation.

The compositions prepared and their attendant results in terms of easeof dispersion, suspension quality and fine particle fraction of aerosolare given in Table V below.

TABLE V Fine Wt. Ratio particle Blend Propellant medicament: Ease ofExtent of Suspension fraction of Example (wt %) (wt %) lactosedispersion aggregation quality aerosol 8 0.29 99.71 1:2.5 f low f/g g 90.91 99.09 1:10 g low f/g g 10 2.15 97.85 1:25 g low f/g g 11 4.21 95.791:50 g low f/g f/g 12 6.77 93.33 1:67 g low f/g f/g 13 8.35 91.65 1:100g low f/g p/f

As can be seen from Table V the ease of dispersion of the blend in thepropellant increased as the proportion of particulate lactose toparticulate medicament increased. At higher levels of particulatelactose to particulate medicament however the measurable fine particlefraction i.e. the particulate medicament of the aerosol decreased.

In the following Examples 14 to 19 the particle size of the particulatelactose was varied to determine its effect. Different size fractions oflactose were achieved by sieving the commercially available product, thesieved fractions were deemed to have particle diameter substantiallyequivalent to the volume diameter. The fraction employed in Example 15comprising lactose particles <38 μm had a median particle size ofapproximately 17 to 18 μm. The mixture contained a weight ratio ofparticulate salbutamol sulphate to lactose of 1:10 and the mixturecomprised in each instance 1.1 wt % of the total composition with thebalance comprising 98.90% propellant to give on each actuation atherapeutic dose of medicament. The results in terms of case ofdispersion, suspension quality and fine particle fraction of aerosol aregiven in Table VI below.

TABLE VI Particle Flue size of Extent particle Exam- material of Ease ofSuspension fraction ple (μm) aggregation dispersion quality of aerosol14  4-400 low g f/g g 15 <38 low g g — 16 38-45 low g g f 17 45-63 low gg f/g 18 63-90 low g f/g f/g 19  90-125 low g f/g f/g

Each of Examples 14 to 19 produced a suspension with good ease ofdispersion properties. The suspension qualities were acceptable in allcases although were superior in the <38, 38 to 45 and 45 to 63 μmranges. The aerosol properties however in terms of fine particlefraction of medicament were better with particulate lactose of thegreater particulate size.

In present Example 20 the fine particle fraction of aerosol tests werecarried out on a metered dosed inhaler, as described above, containingthe composition of Example 9 above to demonstrate the efficacy of thesuspension throughout the life of an inhaler.

The results are given in Table VII below in terms of shot nos. i.e. thecounted actuations of the valve throughout the inhaler's life.

TABLE VII Fine particle fraction Shot nos. of aerosol 4-5 g 41-42 g62-63 g

In present Example 21 the composition of Example 12 above wascentrifuged at 5000 g for 30 mins. The centrifuged suspension wasobserved to demonstrate a good ease of dispersion, a low extent ofaggregation and a fair/good suspension quality. The test was designed todemonstrate the propensity or otherwise of the suspension to aggregateirreversibly or cake over time.

EXAMPLE 22

Example 22 employed ball milled L-Leucine as the second particulatematerial having a sieve fraction of 90 to 125 μm, and salbutamolsulphate as employed in Example S above. The weight ratio of L-Leucineto salbutamol sulphate was 10:1. The mixture was weighed directly intothe canister, the valve crimped, and HFA-134a propellant added in aweight ratio of salbutamol sulphate/leucine: propellant of 1:10. Theactuation dose was 100 μg. The unit was briefly hand shaken prior toeach firing.

The canister was fired in a pattern designed to imitate the potentialuse of metered dose inhaler when used by a potential patient. Thecanister was therefore fired as two shots up to four times daily.Individual shot weights were measured. Aerosol performance and shotpotency were determined at the beginning, middle and end of the life ofthe unit (i.e. on days 0,20 and 42),

Aerosol performance was assessed by measuring fine particle fractionusing a four stage liquid impinger.

Shot potency was determined on individual actuations.

FIG. 3 shows the results of the mean shot weight versus shot number forthe canister collected over 42 days, following nominal actuationtimetable of two shots fired four times daily. The shot weights can beseen to be reasonably reproducible over the 42 days period and are thusan indicator of valve integrity. Few individual shots lie away theintended shot actuation weight. The variation in a patient actuateddevice is deemed acceptable.

FIG. 4 shows in diagrammatic form the shot potency i.e. the drug doseper actuation at the start, middle and end of the lifetime testing shownin FIG. 3. The figure shows reproducible and high recovery of thenominal dose at the beginning, middle and end of the unit life, evenafter storage, when not being tested, at 40° C., 75% R.H. for 42 days.The increased potency of shot 203 is a consequence of a high shotweight. If the potency is normalised for shot weight it is comparablefor the data for the other shots in FIG. 4. The data of FIG. 4 indicatethat a homogeneous suspension is formed from which representativealiquots are measured.

FIG. 5 shows that good aerosol performance was maintained throughout thelife of the canister.

What is claimed is:
 1. Aerosol composition comprising a propellant andcontained therein a first particulate material comprising particleshaving a median aerodynamic diameter within the range 0.05 μm to 11 μmand a second particulate material comprising particles having a medianvolume diameter within the range 15 to 200 μm, wherein the first andsecond particulate materials are segregated upon aerosolization into arespirable first fraction and a non-respirable second fraction. 2.Composition according to claim 1 wherein the second particulate materialhas a median volume diameter within the range 20 to 125 μm. 3.Composition according to claim 1 wherein the weight ratio of firstparticulate material to second particulate material in the compositionlies in the range 1:0.1 to 1:500.
 4. Composition according to claim 3wherein the weight ratio of first particulate material to secondparticulate material in the composition lies in the range 1:10 to 1:100.5. Composition according to claim 1 wherein the first particulatematerial has a median aerodynamic diameter within the range 1 to 10 μm.6. Composition according to claim 1 wherein the second particulatematerial has a Mohs hardness value of less than
 5. 7. Compositionaccording to claim 1 wherein the second particulate material has a CarrIndex value: for particles more than 100 um in size of less than 14%;for particles 40 to 100 um in size of less than 28%; for particles 20 to40 um in size of less than 35%; and for particles less than 20 um insize of less than 65%.
 8. Composition according to claim 1 wherein thesolubility of the first particulate material in the propellant is lessthan 49.9 wt % with respect to the total weight of the substance presentin the composition comprising the first particulate material. 9.Composition according to claim 1 wherein the solubility of the secondparticulate material in the propellant is less than 49.9 wt % withrespect to the total weight of the substance present in the compositioncomprising the second particulate material.
 10. Composition according toclaim 1 wherein the composition comprises at least 80 wt % and up to99.999 wt % propellant.
 11. Composition according to claim 10 whereinthe total of the first and second particulate material comprises atleast 0.001 wt % and up to 20 wt % of the composition.
 12. Compositionaccording to claim 1 further comprising a surfactant, flavouringmaterial, buffer, preservative or any mixture thereof.
 13. Compositionaccording to claim 1 wherein the propellant is selected from the groupconsisting of chlorofluorocarbons, hydrofluorocarbons, and mixturesthereof.
 14. Composition according to claim 13 wherein the propellant isselected from the group consisting of hydrofluorocarbons and mixturesthereof.
 15. Composition according to claim 14 wherein the propellant isa hydrofluoroalkane selected from the group consisting of1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, andmixtures thereof.
 16. Composition according to claim 1 wherein the firstparticulate material is a medicament.
 17. Composition according to claim16 wherein the medicament is selected from the group consisting ofsalbutamol, salbutamol sulphate, terbutaline, terbutaline sulphate,ipratropium bromide or any physiologically acceptable salts or solvatesthereof; beclomethasone diproprionate, budesonide, triamcinoloneacetonide or any physiologically acceptable solvates thereof;corticosteroid, bronchodilator; peptides, proteins, nucleic acids orderivatives thereof; insulin, calcitonin, growth hormone, lutensinghormone releasing hormone, leuprolide, and oxytocin or anyphysiologically acceptable salts or solvates thereof, and any mixturethereof.
 18. Composition according to claim 17 wherein the medicament issalbutamol sulphate.
 19. Composition according to claim 16 wherein themedicament is salmeterol xinafoate or a mixture of salmeterol xinafoatewith any one of the group consisting of salbutamol, salbutamol sulphate,terbutaline, terbutaline sulphate, ipratropium bromide or anyphysiologically acceptable salts or solvates thereof; beclomethasonediproprionate, budesonide, triamcinolone acetonide or anyphysiologically acceptable solvates thereof; corticosteroid,bronchodilator; peptides, proteins, nucleic acids or derivativesthereof; insulin, calcitonin, growth hormone, lutensing hormonereleasing hormone, leuprolide, and oxytocin or any physiologicallyacceptable salts or solvates thereof, and any mixture thereof. 20.Composition according to claim 16 wherein the medicament is fluticasonepropionate or a mixture of fluticasone propionate with any one of thegroup consisting of salbutamol, salbutamol sulphate, terbutaline,terbutaline sulphate, ipratropium bromide or any physiologicallyacceptable salts or solvates thereof; beclomethasone diproprionate,budesonide, triamcinolone acetonide or any physiologically acceptablesolvates thereof; corticosteroid, bronchodilator, peptides, proteins,nucleic acids or derivatives thereof; insulin, calcitonin, growthhormone, lutensing hormone releasing hormone, leuprolide, and oxytocinor any physiologically acceptable salts or solvates thereof, and anymixture thereof.
 21. Composition according to claim 16 wherein themedicament is beclomethasone dipropionate or a physiologicallyacceptable solvate thereof, or any mixture thereof with any one of thegroup consisting of salbutamol, salbutamol sulphate, terbutaline,terbutaline sulphate, ipratropium bromide or any physiologicallyacceptable salts or solvates thereof; beclomethasone diproprionate,budesonide, triamcinolone acetonide or any physiologically acceptablesolvates thereof; corticosteroid, bronchodilator; peptides, proteins,nucleic acids or derivatives thereof; insulin, calcitonin, growthhormone, lutensing hormone releasing hormone, leuprolide, and oxytocinor any physiologically acceptable salts or solvates thereof, and anymixture thereof.
 22. Composition of claim 1 wherein the secondparticulate material is selected from the group consisting of aminoacids, di-, tri-, oligo-, and poly-peptides, proteins, physiologicallyacceptable derivatives, forms, salts, and solvates thereof, and mixturesthereof.
 23. Pharmaceutical composition comprising a propellant andcontained therein a particulate medicament comprising particles having amedian aerodynamic diameter within the range 0.05 to 11 μm and a secondparticulate material comprising particles having a median volumediameter within the range 15 to 200 μm, wherein the second particulatematerial is selected from the group consisting of amino acids, di-,tri-, oligo-, and poly-peptides, proteins, physiologically acceptablederivatives, forms, salts, and solvates thereof, and mixtures thereof,and wherein the particulate medicament and second particulate materialsare segregated upon aerosolization into a respirable first fraction anda non-respirable second fraction.
 24. A method for preparing an aerosolcomposition according to any one of claims 1 to 23 comprising: (a)forming a mixture of the first particulate material and the secondparticulate material; (b) dispensing measured portions of respectivelythe said mixture and the propellant into a container; and (c) sealingthe container.
 25. The method according to claim 24 wherein the mixtureis dispensed into the container before the propellant.
 26. A method forpreparing a composition according to any one of claims 1 to 23comprising admixing the ingredients together prior to dispensing into acontainer and sealing the container.
 27. The method according to claim26 wherein the container includes an outlet valve.
 28. A method ofadministering a particulate medicament to a patient in need thereofcomprising forming an aerosol from the aerosol composition according toany one of claims 18 to 23 and the patient inhaling the aerosol.
 29. Anaerosol composition according to any one of claims 18 to 23 for use inthe treatment of respiratory disorders.
 30. A container containing acomposition according to any one of the preceding claims wherein thecontainer includes a valve outlet.
 31. A container according to claim 30wherein the valve outlet is a metered dose valve.
 32. A containeraccording to claim 31 in the form of a metered dose inhaler.
 33. Aninhalation device incorporating a container according to claim
 30. 34. Amixture of first particulate material having a median aerodynamicdiameter within the range 0.05 to 11 μm and a second particulatematerial having a median volume diameter within the range of 15 to 200μm, wherein the second particulate material is selected from the groupconsisting of amino acids, di-, tri-, oligo-, and poly-peptides,proteins, physiologically acceptable derivatives, forms, salts, andsolvates thereof, and mixtures thereof, and wherein the first and secondparticulate materials are segregated upon aerosolization into arespirable first fraction and a non-respirable second fraction. 35.Aerosol composition comprising a propellant and contained therein afirst particulate material comprising particles having a medianaerodynamic diameter within the range 0.05 μm to 11 μm and a secondparticulate material comprising particles having a median volumediameter within the range 38 to 200 μm.
 36. Composition of claim 35,wherein the second particulate material is a carbohydrate. 37.Composition of claim 36, wherein the carbohydrate is selected from thegroup consisting of sugars, mono-, di-, tri-, oligo-, andpoly-saccharides, and any physiologically acceptable derivatives, salts,forms, and solvates thereof, and any mixtures thereof.
 38. Compositionof claim 35, wherein the second particulate material has a median volumediameter within the range 38 to 63 μm.
 39. Composition of claim 38,wherein the second particulate material has a median volume diameterwithin the range 45 to 63 μm.
 40. Pharmaceutical composition comprisinga propellant and contained therein a particulate medicament comprisingparticles having a median aerodynamic diameter within the range 0.05 to11 μm and a second particulate material comprising particles having amedian volume diameter within the range 38 to 200 μm.
 41. Composition ofclaim 40, wherein the second particulate material is a carbohydrate. 42.Composition of claim 41, wherein the carbohydrate is selected from thegroup consisting of sugars, mono-, di-, tri-, oligo-, andpoly-saccharides, and any physiologically acceptable derivatives, salts,forms, and solvates thereof, and any mixtures thereof.
 43. Compositionof claim 40, wherein the second particulate material has a median volumediameter within the range 38 to 63 μm.
 44. Composition of claim 43,wherein the second particulate material has a median volume diameterwithin the range 45 to 63 μm.
 45. Composition of claim 40, wherein thefirst and second particulate materials are segregated uponaerosolization into a respirable first fraction and a non-respirablesecond fraction.
 46. A mixture of first particulate material having amedian aerodynamic diameter within the range 0.05 to 11 μm and a secondparticulate material having a median volume diameter within the range of38 to 200 μm.
 47. Mixture of claim 46, wherein the second particulatematerial is a carbohydrate.
 48. Mixture of claim 47, wherein thecarbohydrate is selected from the group consisting of sugars, mono-,di-, tri-, oligo-, and poly-saccharides, and any physiologicallyacceptable derivatives, salts, forms, and solvates thereof, and anymixtures thereof.
 49. Mixture of claim 46, wherein the secondparticulate material has a median volume diameter within the range 38 to63 μm.
 50. Mixture of claim 49, wherein the second particulate materialhas a median volume diameter within the range 45 to 63 μm.
 51. Mixtureof claim 46, wherein the first and second particulate materials aresegregated upon aerosolization into a respirable first fraction and anon-respirable second fraction.